Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease

肺部疾病是系统性自身免疫性疾病的常见并发症，通常需要 采用大剂量免疫抑制或肺移植进行积极治疗。增速出现明显 临床上的影响，很少有人了解肺部疾病的发病机制，在自身免疫性条件。作为 加州大学旧金山弗朗西斯科的肺病和重症监护医生Anthony Shum博士是 确立了自己作为自身免疫介导的肺部疾病机制的研究者的地位。与 高度重视免疫学培训计划和国际公认的指导团队，UCSF 为沈博士的关键研究和必要的强化培训提供了理想的环境。 他的职业生涯的长期目标是成为一名医生科学家。主要导师马克博士 安德森，是一个领先的专家在中枢免疫耐受，和共同导师，博士哈罗德查普曼，教授 肺科主任，是肺损伤和组织重塑方面的著名权威。 肺自身免疫研究的一个主要障碍是缺乏研究的动物模型 发病机理Shum博士的研究使用Aire（自身免疫调节因子）缺陷小鼠， 提供了独特的机会，以确定在一个新的模型中的自身免疫性肺病的基本机制 一种已知的人类自身免疫综合征自身免疫性多腺综合征1（APS 1）由以下原因引起： Aire基因的突变，像他们的人类同行，Aire缺陷小鼠发展自身免疫， 多个器官，包括肺，由于中枢免疫耐受性的严重破坏。重要的是， Aire缺陷小鼠自发发生间质性肺病，其模式与APS 1惊人相似 患者此外，Shum博士已经在Aire缺陷小鼠中鉴定出一种新的肺自身抗原， 是引发疾病的关键因此，我们假设Aire基因敲除小鼠的肺部疾病是由于 胸腺细胞不能耐受一种关键的肺抗原，导致自身反应性T细胞逃逸， 瞄准并伤害肺部为了解决这一假设，提出的具体目标是：（1）确定 在Aire KO小鼠中介导肺部疾病的细胞群;（2）建立我们的肺抗原在 小鼠模型中肺部疾病的发病机制;和（3）建立人同源物的作用 相关性（见说明）。在这个项目中，我们将学习如何肺损伤发生在系统性自身免疫性 类风湿性关节炎或硬皮病。我们将识别攻击肺部的细胞， 它们所针对的肺部蛋白质以及它们如何造成损伤。这样做，我们将能够开发血液 测试，以帮助医生诊断患有自身免疫性肺病的患者，并确定他们的预后。我们 还寻求设计专门针对肺部的疗法，以有效治疗患有这些疾病的患者。

Pulmonary disease is a frequent complication of systemic autoimmune diseases, often requiring aggressive treatment with high dose immunosuppression or lung transplantation. Despite the significant clinical impact, little is understood about the pathogenesis of lung disease in autoimmune conditions. As a pulmonary and critical care physician at the University of California, San Francisco, Dr. Anthony Shum is establishing himself as an investigator in the mechanisms of autoimmune-mediated lung disease. With the highly regarded Immunology Training Program and an internationally recognized mentoring team, UCSF provides the ideal environment for the critical studies and intensive training necessary for Dr. Shum's development towards his long-term goal of a career as a physician-scientist. The primary mentor, Dr. Mark Anderson, is a leading expert in central immune tolerance, and co-mentor, Dr. Harold Chapman, Professor and Chief of the Pulmonary Division, is a renowned authority on lung injury and tissue remodeling. A major barrier to research on lung autoimmunity has been the lack of animal models in which to study disease pathogenesis. Using the Aire (Autoimmune Regulator) deficient mouse, Dr. Shum's research presents the unique opportunity to define basic mechanisms of autoimmune lung disease in a novel model of a known human autoimmune syndrome. Autoimmune Polyglandular Syndrome 1 (APS1) arises from mutations in the AIRE gene and like their human counterparts, Aire deficient mice develop autoimmunity to multiple organs, including the lung, due to a critical breakdown in central immune tolerance. Importantly, Aire deficient mice develop interstitial lung disease spontaneously in a pattern strikingly similar to APS1 patients. Furthermore, Dr. Shum has identified a novel lung autoantigen in the Aire deficient mouse that may be the key to initiating disease. Thus, we hypothesize that pulmonary disease in Aire KO mice is due to a failure to tolerize thymocytes to a critical lung antigen, resulting in the escape of autoreactive T cells that target and injure the lung. To address this hypothesis, the proposed specific aims are to: (1) determine the cell populations that mediate lung disease in Aire KO mice; (2) establish the role of our lung antigen in the pathogenesis of pulmonary disease in the mouse model; and (3) establish the role of the human homolog of RELEVANCE (Seeinstructions). In this project we will learn how lung damage occurs in systemic autoimmune diseases like rheumatoid arthritis or scleroderma. We will identify the cells that are attacking the lung, which lung proteins they are targeting, and how they cause injury. In doing so, we will be able to develop blood tests to help physicians diagnose patients with autoimmune lung disease and determine their prognosis. We also seek to design therapies made specifically for the lung to effectively treat patients with these disorders.